Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability

Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31231217/In cystic fibrosis, the most common disease-causing mutation is F508del, which causes not only intracellular retention and degradation of CFTR, but also defective channel gating and decreased membrane stability of the small amount that reaches the plasma membrane (PM). Thus, pharmacological correction of mutant CFTR requires targeting of multiple cellular defects in order to achieve clinical benefit. Although small-molecule compounds have been identified and commercialized that can correct its folding or gating, an efficient retention of F508del CFTR at the PM has not yet been explored pharmacologically despite being recognized as a crucial factor for improving functional rescue of chloride transport. In ongoing efforts to determine the CFTR interactome at the PM, we used three complementary approaches: targeting proteins binding to tyrosine-phosphorylated CFTR, protein complexes involved in cAMP-mediated CFTR stabilization at the PM, and proteins selectively interacting at the PM with rescued F508del-CFTR but not wt-CFTR. Using co-immunoprecipitation or peptide-pull down strategies, we identified around 400 candidate proteins through sequencing of complex protein mixtures using the nano-LC Triple TOF MS technique. Key candidate proteins were validated for their robust interaction with CFTR-containing protein complexes and for their ability to modulate the amount of CFTR expressed at the cell surface of bronchial epithelial cells. Here, we describe how we explored the abovementioned experimental datasets to build a protein interaction network with the aim of identifying novel pharmacological targets to rescue CFTR function in cystic fibrosis (CF) patients. We identified and validated novel candidate proteins that were essential components of the network but not detected in previous proteomic analyses.This work was supported by FCT, Portugal, through center grant UID/MULTI/04046/2019 to BioISI and the BioSys PhD program PD65-2012 (fellowships SFRH/BD/52488/2014, SFRH/ BD/106084/2015, and SFRH/BD/52490/2014 to CL, JS, and AM, respectively).info:eu-repo/semantics/publishedVersio

A Novel p.Leu213X Mutation in GJB2 Gene in a Portuguese Family

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Assessing the intestinal permeability and anti-inflammatory potential of sesquiterpene lactones from chicory

Funding: This research and the article processing cost were funded by EU Horizon 2020 research & innovation programme under grant agreement N. 760891 project CHIC. M.S.M. also acknowledges the financial support from Fundação para a Ciência e Tecnologia for her PhD scholarship (SFRD/BD/145551/2019).Cichorium intybus L. has recently gained major attention due to large quantities of health-promoting compounds in its roots, such as inulin and sesquiterpene lactones (SLs). Chicory is the main dietary source of SLs, which have underexplored bioactive potential. In this study, we assessed the capacity of SLs to permeate the intestinal barrier to become physiologically available, using in silico predictions and in vitro studies with the well-established cell model of the human intestinal mucosa (differentiated Caco-2 cells). The potential of SLs to modulate inflammatory responses through modulation of the nuclear factor of activated T-cells (NFAT) pathway was also evaluated, using a yeast reporter system. Lactucopicrin was revealed as the most permeable chicory SL in the intestinal barrier model, but it had low anti-inflammatory potential. The SL with the highest anti-inflammatory potential was 11β,13-dihydrolactucin, which inhibited up to 54% of Calcineurin-responsive zinc finger (Crz1) activation, concomitantly with the impairment of the nuclear accumulation of Crz1, the yeast orthologue of human NFAT.publishersversionpublishe

Persistent organic pollutant levels in human visceral and subcutaneous adipose tissue in obese individuals - Depot differences and dysmetabolism implications

Background: The role of persistent organic pollutants (POPs) with endocrine disrupting activity in the aetiology of obesity and other metabolic dysfunctions has been recently highlighted. Adipose tissue (AT) is a common site of POPs accumulation where they can induce adverse effects on human health. Objectives: To evaluate the presence of POPs in human visceral (vAT) and subcutaneous (scAT) adipose tissue in a sample of Portuguese obese patients that underwent bariatric surgery, and assess their putative association with metabolic disruption preoperatively, as well as with subsequent body mass index (BMI) reduction. Methods: AT samples (n=189) from obese patients (BMI ≥35) were collected and the levels of 13 POPs were determined by gas chromatography with electron-capture detection (GC-ECD). Anthropometric and biochemical data were collected at the time of surgery. BMI variation was evaluated after 12 months and adipocyte size was measured in AT samples. Results: Our data confirm that POPs are pervasive in this obese population (96.3% of detection on both tissues), their abundance increasing with age (RS=0.310, p<0.01) and duration of obesity (RS=0.170, p<0.05). We observed a difference in AT depot POPs storage capability, with higher levels of ΣPOPs in vAT (213.9±204.2 compared to 155.1±147.4 ng/g of fat, p<0.001), extremely relevant when evaluating their metabolic impact. Furthermore, there was a positive correlation between POP levels and the presence of metabolic syndrome components, namely dysglycaemia and hypertension, and more importantly with cardiovascular risk (RS=0.277, p<0.01), with relevance for vAT (RS=0.315, p<0.01). Finally, we observed an interesting relation of higher POP levels with lower weight loss in older patients. Conclusion: Our sample of obese subjects allowed us to highlight the importance of POPs stored in AT on the development of metabolic dysfunction in a context of obesity, shifting the focus to their metabolic effects and not only for their recognition as environmental obesogens

Inflammatory and Cardiometabolic Risk on Obesity: Role of Environmental Xenoestrogens

Some chemicals used in consumer products or manufacturing (eg, plastics, pesticides) have estrogenic activities; these xenoestrogens (XEs) may affect immune responses and have recently emerged as a new risk factors for obesity and cardiovascular disease. However, the extent and impact on health of chronic exposure of the general population to XEs are still unknown.info:eu-repo/semantics/publishedVersio

Analysis of the Impact of Size of Brain Metastases in the Overall Survival of Patients with Primary Head and Neck Cancer, Melanoma and Sarcoma

peer reviewe

Estimation of genetic parameters for reproductive traits evaluated by ultrasonography in Senepol heifers

Studies on reproductive tract score (RTS) and antral follicle count (AFC) in Senepol cattle are limited. These traits are essential as they are linked to the reproductive ability and reproductive performance of animals. Understanding the heritability and genetic correlation of these traits is crucial for guiding selection programs and selecting animals with greater reproductive efficiency and higher production potential. Therefore, this study aimed to estimate the genetic parameters of weight, RTS, and AFC in Senepol cattle using transrectal ultrasonography. Reproductive data were collected from 850 female Senepol cattle aged 10-16 months. At the time of evaluation, the following were measured: RTS traits (scores from 1 to 5), AFC (0 to 100), and female weight (kg). Variance and covariance components, genetic heritability, and correlations were estimated by univariate and bivariate analyses using the bull model. Heritability estimates were moderate for AFC (0.52) and weight (0.46), and low for RTS (0.12). The genetic correlation between RTS and AFC was almost zero (-0.05). The estimated genetic correlation between weight and AFC was -0.41, while the correlation between weight and RTS was 0.48. Selective breeding of AFC and RTS can enhance the reproductive efficiency of the herd and result in animals with earlier pubertal age and increased fertility

Abordagem geriátrica ampla na promoção de um envelhecimento ativo e saudável: componentes do modelo de intervenção AGA@4life

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ESTILO DE VIDA E CONDIÇÃO METABÓLICA DE MULHERES DIABÉTICAS E/OU HIPERTENSAS DE UMA REGIÃO URBANA

A presente investigação objetivou relacionar o estilo de vida com a condição metabólica de mulheres atendidas no Centro de Atendimento ao Diabético e Hipertenso na cidade de Feira de Santana/BA. Realizou-se um estudo transversal com 259 mulheres adultas, no qual foi traçado o perfil sociodemográfico, de condição de saúde e estilo de vida das participantes a partir de um formulário e por meio de entrevista. O desfecho foi determinado conforme a presença da Síndrome Metabólica (SM). Foram obtidas frequências simples e relativas. A comparabilidade entre os grupos foi feita com o teste qui-quadrado de Pearson ou Exato de Fisher, com nível de significância de 5%. A SM estava presente em 71,81% das participantes. E a média da idade foi 59 ± 13,1 anos. Mulheres não brancas com renda ≥ 1 salário mínimo apresentaram indicadores mais elevados de SM. O consumo de álcool e fumo, a prática de atividade física e o autocuidado bucal foram considerados baixos e todos os componentes da SM mostraram diferenças significantes entre os grupos, exceto a glicemia de jejum. Observaram frequências altas de SM. No entanto a amostra não teve poder suficiente para detectar a real influência de características de estilo de vida na sua ocorrência

Randomized controlled trial of an Acceptance and Commitment Therapy and compassion-based group intervention for persons with inflammatory bowel disease: the LIFEwithIBD intervention

ObjectivesThis study tested the acceptability and efficacy of an Acceptance and Commitment Therapy and compassion-based intervention (LIFEwithIBD) in people with IBD through a two-arm RCT.MethodsParticipants were recruited at the Gastroenterology Department of the Coimbra University Hospital between June and September 2019. Of the 355 patients screened, those who accepted to participate were randomly assigned to one of two conditions: experimental group (LIFEwithIBD; n = 25) or control group (waitlist; n = 29). Participants completed self-report measures at baseline (T0), post-intervention (T1), and 3-month (T2) and 12-month (T3) follow-ups. Intervention acceptability was assessed. Efficacy was examined using intent-to-treat ANCOVA at post-intervention after adjusting for baseline values of depressive, anxiety, and stress symptoms (primary outcomes). Linear mixed models for all longitudinal outcomes were also analysed. Inflammatory and disease biomarkers were determined at T0 and T3.ResultsAcceptability results revealed a high level of satisfaction and perceived usefulness regarding the intervention. Both groups experienced a significant decrease in stress symptoms and IBD symptom perception at T1. No significant differences were observed at follow-up for the primary outcomes. The experimental group reported significantly lower Crohn’s disease Symptom severity at T2 than the control group. Post-hoc analyses designed to mitigate floor effects revealed substantial treatment effects for the experimental group regarding anxiety symptoms. No significant differences were observed in clinical biomarkers from T0 to T3.ConclusionThe LIFEwithIBD intervention shows promising, although preliminary, benefits for managing disease activity and reducing anxiety symptoms in IBD patients with high severity of psychological distress.Clinical trial registration: https://www.clinicaltrials.gov/ct2/show/NCT03840707, identifier NCT03840707